The present invention relates to hexafluoroisopropanol derivatives, to pharmaceutical compositions comprising the same and to the use of these hexafluoroisopropanol derivatives in the treatment of atherosclerosis.
The Liver X Receptors (LXRs) are a family of nuclear receptors that are activated upon binding of the naturally occurring oxysterols inducing transcription of target genes. Two subtypes of LXR (α and β) have been identified and exhibit 77% homology of both their ligand- and DNA-binding domains. Both subtypes are highly conserved between humans and rodents however their tissue expression patterns differ significantly. The expression of LXRα is restricted to tissues involved in lipid metabolism with highest expression in the liver; there are also significant levels in kidney, spleen, small intestine and adipose tissue. LXRβ is very widely distributed and has been found in virtually every tissue examined, including liver and brain. Both LXRβ and LXRβ are expressed in macrophages. See Costet et al., J. Biol. Chem. 275:28240-28245 (2000).
The roles of the LXR receptors are not fully understood, however LXR is well established as a master regulator of lipid metabolism in the liver and peripheral tissues, and as the key inducer of the ATP-binding cassette transporter A1 (ABCA1) gene (Venkateswaran et al., Proc. Natl. Acad. Sci. USA. 97:12097-12102 (2000)). In the human population, mutations of the ABCA1 gene lead to highly atherogenic lipoprotein profiles (Singaraja et al., Arterioscier. Thromb. Vasc. Biol. 23:1322-1332 (2003)) which in the most severe form cause Tangier's Disease and associated premature atherosclerosis, (see Bodzioch et al., Nat. Genet. 22:347-351 (1999) and Rust et al., Nat. Genet. 22:352-355 (1999)). This rare inherited disorder is characterised by very low levels of high density lipoproteins (HDL), macrophage accumulation of cholesterol esters and significantly increased risk of atherosclerotic disease (Brooks-Wilson et al., Nat. Genet. 22:336-345 (1999)). Evidence has demonstrated that up-regulation of ABCA1 in human macrophages and enterocytes of the small intestine, is mediated by LXR activation (Costet et al., supra). Furthermore, LXR agonists have also been shown to promote cholesterol efflux. See Claudel et al., Proc. Natl. Acad. Sci. USA. 98:2610-2615 (2001). LXR receptors therefore play a critical role in cholesterol homeostasis in macrophages, and suppression within the local environment of the advanced atherosclerotic plaque may be a key feature of the pathology of the disease.
The potential utility of LXR agonists in the treatment of atherosclerosis has been increasingly documented over the last few years. See for example Levin et al., Arterioscler. Thromb. Vasc. Biol. 25:135-142 (2005). Atherosclerosis is a disease of the arteries that exists for many years without causing symptoms. Advanced atherosclerotic plaques can however become vulnerable to rupture, promoting acute thrombosis and clinical events such as myocardial infarction (MI) and stroke. The primary cell type implicated in rupture of atherosclerotic plaques, and subsequent clinical events, is the macrophage. The primary mechanism for achieving efficacy in atherosclerosis with an LXR agonist is expected to occur by lowering the cholesterol burden of arteries (via upregulation of ABCA1), to generate more stable lesions and thus reduce the clinical events. Additionally, LXR agonists may increase circulating HDL levels due to the role of ABCA1 in generation of nascent HDL by the liver. There is potential for further anti-atherosclerotic effects of LXR agonists due to suppression of inflammation (Joseph et al., Nat. Med. 9:213-219 (2003)) and effects on glucose metabolism. See Latiffe et al., Proc. Natl. Acad. Sci. USA. 100:5419-24 (2003).
The first compounds specifically identified as LXR agonists for the treatment of atherosclerosis were disclosed by Tularik, Inc. (International Patent Application WO 00/54759) and contain the hexafluoroisopropanol group. Since then a number of different chemotypes have been identified as LXR agonists (for a review see: Bennett et al. Expert Opin. Ther. Patents 16, 1673-1699, 2006).
There is a remaining need for compounds that are effective as LXR modulators.
To this aim the present invention provides hexafluoroisopropanol derivatives having the general Formula I
wherein    B represents a five or six membered aromatic ring which is substituted at a carbon atom by a hexafluoroisopropanol moiety, the ring optionally comprising one or two nitrogens, sulphur or oxygen;    n is 1 or 2;    Z is CH2 or CO;    Y is CO, SO2, CH2 or a bond; and can be of meta or para substitution pattern;    A is a 6-membered aromatic ring optionally containing 1 or 2 nitrogen atoms;    X is NR4, O or a bond;    W is NH, O or CH2;    R1 is (C1-8)alkyl, (C3-8)cycloalkyl or (C3-8)cycloalkyl(C(1-4)alkyl, each of the alkyl groups being optionally substituted with hydroxyl, hydroxymethyl, (C1-3)alkyloxy, cyano, halogen, CF3, NR7R8, NR7R8CO or R9OCO; or    R1 is 5- or 6-membered aromatic ring, optionally comprising 1-3 heteroatoms selected from O, S and N, the ring being optionally substituted by (C1-3)alkyl, (C3-6)cycloalkyl, (C1-3)alkyloxy, (C1-3)alkylsulfonyl, cyano, CF3, OCF3, halogen or R9OCO, and the ring being optionally linked to X via a (C1-3)alkylene group which is optionally substituted by hydroxyl; or    R1 is a 5- or 6-membered saturated or unsaturated heterocyclic ring, comprising 1 or 2 heteroatoms selected from NR10, O, S, SO and SO2, the ring being optionally substituted by (C1-3)alkyl, hydroxyl, oxo, NR11R12CH2 or R9OCO, and the ring being optionally linked to X via a (C1-3)alkylene group which is optionally substituted by hydroxyl; or    when X is NR4, R1 may together with R4 and the N to which they are bonded form a 4-8 membered ring, which can be optionally substituted with hydroxyl or hydroxymethyl;    R2 optionally represents 1-3 substituents independently selected from (C1-4)alkyl, (C1-4)alkyloxy, CF3, OCF3 and halogen;    R3 optionally represents 1-4 substituents independently selected from (C1-4)alkyl and (C1-4)alkyl substituted by OH or 1 or more halogens; or    R3 represents oxo or COOR5;    R4, when present is H or (C1-3)alkyl;    R5, when present is H or (C1-3)alkyl;    R6, when present is H or (C1-3)alkyl;    R7 and R8, when present, are independently H, (C1-3)alkyl or (C3-5)cycloalkyl;    R9, when present, is H, (C1-3)alkyl or (C3-5)cycloalkyl(C1-3)alkyl;    R10, when present, is H, (C1-3)alkyl or CO(C1-3)alkyl;    R11 and R12, when present, are independently H or (C1-3)alkyl;    or a pharmaceutically acceptable salt thereof.
In one aspect the invention provides hexafluoroisopropanol derivatives having the general Formula II
wherein    n is 1 or 2;    A is a 6-membered aromatic ring optionally containing 1 or 2 nitrogen atoms;    X is NR4, O or a bond;    R1 is (C1-8)alkyl, (C3-8)cycloalkyl or (C3-8)cycloalkyl(C(1-4)alkyl, each of the alkyl groups being optionally substituted with hydroxyl or hydroxymethyl; or    when X is NR4, R1, may together with R4 and the N to which they are bonded form a 4-8 membered ring, which can be optionally substituted with hydroxyl or hydroxymethyl;    R2 optionally represents 1-3 substituents independently selected from (C1-4)alkyl, (C1-4)alkyloxy, CF3 and halogen;    R3 optionally represents 1-4 substituents independently selected from (C1-4)alkyl and (C1-4)alkyl substituted by OH or 1 or more halogens;    R4, when present is H or (C1-3)alkyl;    or a pharmaceutically acceptable salt thereof.
Compounds according to Formula II correspond to certain of the compounds of Formula I wherein W represents NH, Y represents CO, Z represents CH2, and ring B represents phenyl.
N-Benzyl, N′-arylcarbonylpiperazine derivatives, which are structurally related to the compounds of the present invention, have been disclosed in U.S. Pat. No. 5,286,728 (Ciba Geigy AG) as inhibitors of the biosynthesis of interleukin-1 (IL-1), useful in the treatment of diseases in which excess production of IL-1 plays a role, such as in inflammatory disorders.
The term (C1-8)alkyl as used in the definition of Formula I means a branched or unbranched alkyl group having 1-8 carbon atoms, like octyl, hexyl, pentyl, isopentyl, butyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl and methyl.
The term (C1-4)alkyl as used in the definition of Formula I means a branched or unbranched alkyl group having 1-4 carbon atoms, like butyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl and methyl.
Likewise, the term (C1-3)alkyl used in the definition of Formula I means a branched or un-branched alkyl group having 1-3 carbon atoms, like propyl, isopropyl, ethyl and methyl.
The term (C3-8)cycloalkyl means a cycloalkyl group having 3-8 carbon atoms, like cycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl and cyclopropyl.
In the term (C3-8)cycloalkyl(C(1-4)alkyl, (C3-8)cycloalkyl and (C1-4)alkyl have the meaning as given above. In addition the term (C3-8)cycloalkyl(C(1-4)alkyl encompasses compounds in which one of the cycloalkyl carbon atom is a spiro-carbon atom, such as 2-methyl-2-cyclopropylethyl and (1-methylcyclobutyl)methyl and the like.
The term (C1-3)alkylene means an alkanediyl functional group such as methylene, 1,2-ethanediyl, 1,3-propanediyl or 2-propanediyl.
The term 5- or 6-membered aromatic ring, optionally comprising 1-3 heteroatoms selected from O, S and N, as used in the definition of R1 is exemplified by ring systems such as phenyl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyrazin-2-yl, pyrimidin-4-yl, 1H-pyrazol-5-yl, pyridazin-4-yl, furan-2-yl, thien-2-yl, oxazol-3-yl, thiazol-2-yl, 1,3,4-thiaziazol-2-yl, 1,2,4-thiadiazol-5-yl, 1,2,4-oxadiazol-5-yl and the like.
The term 5- or 6-membered saturated or unsaturated heterocyclic ring, comprising 1 or 2 heteroatoms selected from NR10, O, S, SO and SO2, as used in the definition of R1 is exemplified by tetrahydro-2H-pyran-4-yl, tetrahydro-2H-furan-2-yl, tetrahydrothiophen-3-yl, imidazolidin-1-yl, morpholin-1-yl, pyrrolidin-1-yl, piperidinyl, pyrrolidinyl, 1,2-dioxo-tetrahydro-1λ6-thiophen-3-yl and the like.
The term a five or six membered aromatic ring optionally comprising one or two nitrogens, sulphur or oxygen, as used in the definition of ring B, is exemplified by phenyl, thiazolyl, oxazolyl, pyridinyl, pyrazinyl, pyrimidinyl, 1H-pyrazolyl, thienyl, oxazoyl, thiazolyl, thiazolyl, thiadiazolyl, oxadiazolyl and the like. The preferred group B is phenyl. In these preferred compounds the hexafluoroisopropanol moiety at the phenyl group of the compounds of Formula I can be positioned at either the ortho, the meta or the para position, the para-position being the preferred one.
The term halogen means F, Cl, Br or I.
There is a preference for hexafluoroisopropanol derivatives of Formula I wherein B represents substituted phenyl.
Further preferred are the hexafluoroisopropanol derivatives of Formula I wherein Z is CH2, Y is CO, W is NH, X is NH and n is 1.
Also preferred are hexafluoroisopropanol derivatives of Formula I, wherein in addition A is a phenyl ring and Y and W are in para-position to each other.
More preferred are the compounds of Formula I wherein R2 represents F or Cl ortho to the W═NH-position; and wherein R3 and R6 are absent.
Particular hexafluoroisopropanol derivatives of the invention are:    1-(cyclopropylmethyl)-3-(4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)-piperazine-1-carbonyl)phenyl)urea;    1-butyl-3-(4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)urea;    1-(4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-isobutylurea;    1-cyclobutyl-3-(4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)urea;    1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(2-hydroxy-2-methylpropyl)urea;    1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(3-hydroxy-3-methylbutyl)urea;    1-(cyclopropylmethyl)-3-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)urea;    (S)-1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(2-hydroxypropyl)urea;    (R)-1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(2-hydroxypropyl)urea;    1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-((1-hydroxycyclopropyl)methyl)urea;    (S)-1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(1-hydroxy-3-methylbutan-2-yl)urea;    1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(4-hydroxycyclohexyl)urea, trans;    (S)-1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(1-hydroxypentan-2-yl)urea;    1-(2-chloro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(2-hydroxy-2-methylpropyl)urea;    (S)-1-(2-chloro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(2-hydroxypropyl)urea;    (R)-1-(2-chloro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(2-hydroxypropyl)urea;    1-(2-chloro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(3-hydroxy-3-methylbutyl)urea;    1-(2-chloro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-((1-hydroxycyclopropyl)methyl)urea; and    1-(2-chloro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(4-hydroxycyclohexyl)urea, trans;    1-(2-amino-2-methylpropyl)-3-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)urea;    1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-((1S,2R)-2-hydroxycyclopentyl)urea;    1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(3-hydroxycyclobutyl)urea, trans;    1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-((1-hydroxycyclobutyl)methyl)urea;    1-(2-(dimethylamino)-2-methylpropyl)-3-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)urea;    1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(3,3,3-trifluoro-2-hydroxypropyl)urea;    1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(tetrahydro-2H-pyran-4-yl)urea;    (R)-1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(2-hydroxy-2-phenylethyl)urea;    (S)-1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(2-hydroxy-2-phenylethyl)urea;    (S)-1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(6-oxopiperidin-3-yl)urea;    1-(2-fluoro-4-{4-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-benzyl]-piperazine-1-carbonyl}-phenyl)-3-(4-hydroxy-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-urea, cis racemate;    1-(1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-3-(2-fluoro-4-{4-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-benzyl]-piperazine-1-carbonyl}-phenyl)-urea;    (R)-1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(tetrahydrofuran-3-yl)urea;    1-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-(2-fluoro-4-{4-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-benzyl]-piperazine-1-carbonyl}-phenyl)-urea;    1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)urea;    (S)-1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(tetrahydrofuran-3-yl)urea;    1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(4-hydroxytetrahydrofuran-3-yl)urea, cis racemate;    1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-((1S,2R)-2-hydroxycyclohexyl)urea, cis racemate;    1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(2-hydroxybutyl)urea, racemate;    1-(2-chloro-4-{4-[4-FA(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-benzyl]-piperazine-1-carbonyl}-phenyl)-3-(4-hydroxy-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-urea, cis racemate;    1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)urea;    1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(2-methylpyridin-4-yl)urea;    1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(2-(trifluoromethyl)pyridin-4-yl)urea;    1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(5-methylisoxazol-3-yl)urea;    1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(3-fluoropyridin-4-yl)urea;    1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(1,3,4-thiadiazol-2-yl)urea;    1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(pyridin-4-yl)urea;    1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(isoxazol-3-yl)urea;    1-(5-cyanothiazol-2-yl)-3-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)urea;    1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(isoxazol-4-yl)urea;    1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(pyridin-2-yl)urea;    1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(3-methylisoxazol-5-yl)urea;    1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(3-methyl-1,2,4-oxadiazol-5-yl)urea;    1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(pyridin-3-yl)urea;    1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(pyrimidin-4-yl)urea;    1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(pyrazin-2-yl)urea;    1-(2-fluoro-4-{4-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-benzyl]-piperazine-1-carbonyl}-phenyl)-3-(1-oxo-tetrahydro-thiopyran-4-yl)-urea; and    1-(2-fluoro-4-{4-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-benzyl]-piperazine-1-carbonyl}-phenyl)-3-(1-oxo-tetrahydro-thiophen-3-yl)-urea; or a pharmaceutically acceptable salt thereof.
The hexafluoroisopropanol derivatives of the invention can be prepared using general synthetic methods known in the art of organic synthesis, for instance by using synthetic routes depicted in Schemes 1-6. Those skilled in the art will know that the order of addition of the key building blocks according to Formulas 2-21 can be altered and still give the desired products of Formula I. Reaction Schemes 1-2 represent two general methods for synthesising the intermediate alkylating agents of Formula 5 and acid derivatives of Formula 6, starting with an amine intermediate of Formula 2 and an ester derivative of Formula 7 respectively. Reaction Scheme 3 gives general conditions for converting the intermediate alkylating agents of Formula 5 and acid derivatives of Formula 6 into the (homo)piperazine derivatives of Formula 11. The (homo)piperazine derivatives of Formula 11 are then used in reaction Schemes 4-6 to synthesise compounds of the invention according to Formula I, using the general methods described. More specifically, reaction Scheme 4 is utilised when W═NH, reaction Scheme 5 is utilised when W═O and reaction Scheme 6 is utilised when W═CH2, to give compounds of the invention according to Formula I.
Conditions:    (1) hexafluoroacetone trihydrate, p-toluenesulfonic acid monohydrate, heat;    (2) dioxane, water, hydrobromic acid (48% weight in water), sodium nitrite, copper (I) bromide;    (3)(a) anhydrous tetrahydrofuran, −78° C., n-butyl lithium in hexane (2.5M), N,N-dimethylformamide;    (b) sodium borohydride, methanol, dichloromethane;    (c) When L is OSO2Me: methanesulfonyl chloride, dichloromethane, triethylamine, 0° C.;    (4) anhydrous tetrahydrofuran, −78° C., n-butyl lithium in hexane (2.5M), carbon dioxide.
Conditions:    (5) cesium fluoride, (trifluoromethyl)trimethylsilane, N,N-dimethylformamide;    (6) When L is Br: N-bromosuccinimide, 2,2′-azobis(isobutyronitrile), CCl4, reflux;    (7) potassium permanganate, water, elevated temperature.
Conditions:    (8) Formula 9, potassium carbonate, acetonitrile, room or elevated temperature;    (9) Formula 9, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride or 1-propanephosphonic acid cyclic anhydride, dichloromethane, triethylamine;    (10) trifluoroacetic acid, dichloromethane.
Conditions:    (11) Formula 12, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride or 1-propanephosphonic acid cyclic anhydride, dichloromethane, triethylamine;    (12)(a) Formula 13, dichloromethane, pyridine;    (b) palladium on carbon, ethyl acetate, hydrogen or iron powder, isopropanol, hydrochloric acid, reflux;    (13)(a) Formula 14, acetonitrile, potassium carbonate, room or elevated temperature    (b) palladium on carbon, ethyl acetate, hydrogen or iron powder, isopropanol, hydrochloric acid, reflux;    (14)(a) Formula 15, tris(dibenzylideneacetone)dipalladium(0), 2-(dicyclohexylphosphino)-biphenyl, sodium tert-butoxide, toluene, heat;    (b) palladium on carbon, ethyl acetate, hydrogen or iron powder, isopropanol, hydrochloric acid, reflux;    (15) When X is NH, NR4 or O: 4-nitrophenyl chloroformate or (bis(trichloromethyl)-carbonate (triphosgene), dichloromethane, and an amine of Formula R1NH2, an amine of Formula R1R4NH or excess alcohol of Formula R1OH, respectively;    When X is bond: dichloromethane, triethylamine, and an acid chloride of Formula R1CO2Cl.
Conditions:    (16) Formula 17, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride or 1-propanephosphonic acid cyclic anhydride, dichloromethane, triethylamine;    (17) Formula 18, dichloromethane, pyridine;    (18) Formula 19, acetonitrile, potassium carbonate, room or elevated temperature;    (19) Formula 20, tris(dibenzylideneacetone)dipalladium(0), 2-(dicyclohexylphosphino)-biphenyl, sodium tert-butoxide, toluene, heat;    (20) When X is NH, NR4 or O: 4-nitrophenyl chloroformate or (bis(trichloromethyl)carbonate (triphosgene), dichloromethane, and an amine of Formula R1NH2, an amine of Formula R1R4NH or excess alcohol of Formula R1OH, respectively;
When X is bond: dichloromethane, triethylamine, and an acid chloride of Formula R1CO2Cl.
Conditions:    (21) Formula 22, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride or 1-propanephosphonic acid cyclic anhydride, dichloromethane, triethylamine;    (22) Formula 23, dichloromethane, pyridine;    (23) Formula 24, acetonitrile, potassium carbonate, room or elevated temperature;    (24) Formula 25, tris(dibenzylideneacetone)dipalladium(0), 2-(dicyclohexylphosphino)-biphenyl, sodium tert-butoxide, toluene, heat;    (25) When X is NH or NR4 or O: (a) Formula 26, lithium hydroxide tetrahydrofuran/methanol/water mixture    (b) N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride or 1-propanephosphonic acid cyclic anhydride, dichloromethane, triethylamine and an amine of Formula R1NH2, an amine of Formula R1R4NH or an excess alcohol of Formula R1OH, respectively;    When X is Bond: (a) Formula 26, lithium hydroxide tetrahydrofuran/methanol/water mixture    (b) N-methoxy-N-methyl amine, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride or 1-propanephosphonic acid cyclic anhydride, dichloromethane, triethylamine    (c) a Grignard reagent of Formula R1MgBr, tetrahydrofuran.
The amine derivatives of Formula 2, the ester derivatives of Formula 7, the (homo)-piperazine derivatives of Formula 9, the acid derivatives of Formulae 12, 17 and 22, the sulfonyl chloride derivatives of Formulae 13, 18 and 23, and the bromide derivatives of Formulae 14, 15, 19, 20, 24 and 25 are compounds that can be prepared using methods well known in the art from commercially available intermediates.
The term O-protecting group, as used above, means a group commonly used for the protection of a hydroxyl group, like tert-butyldimethylsilyl or methyl. Removal of these and other protecting groups can take place in different ways, depending on the nature of those protecting groups. An overview of protecting groups and methods for their removal is given in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, 2nd edition, 1991, John Wiley & Sons, Inc.
The hexafluoroisopropanol derivatives of Formula I and their salts may contain at least one centre of chirality, and exist therefore as stereoisomers, including enantiomers and diastereomers. The present invention includes the aforementioned stereoisomers within its scope and each of the individual R and S enantiomers of the compounds of Formula I and their salts, substantially free, i.e. associated with less than 5%, preferably less than 2%, in particular less than 1% of the other enantiomer, and mixtures of such enantiomers in any proportions including the racemic mixtures containing substantially equal amounts of the two enantiomers. Methods for asymmetric synthesis whereby the pure stereoisomers are obtained are well known in the art, e.g. synthesis with chiral induction or starting from chiral intermediates, enantioselective enzymatic conversions, separation of stereoisomers or enantiomers using chromatography on chiral media. Such methods are for example described in Chirality in Industry (edited by A. N. Collins, G. N. Sheldrake and J. Crosby, 1992; John Wiley).
The present invention also embraces isotopically-labelled hexafluoroisopropanol derivatives of Formula I which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively.
Certain isotopically-labelled compounds of Formula (I) (e.g., those labelled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. 11C and 18F are the preferred isotopes to be incorporated in a compound of the invention for use as a PET (Positron Emission Tomography) tracer. Isotopically labelled compounds of Formula (I) can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.
Pharmaceutically acceptable salts may be obtained by treating a free base of a compound of Formula I with a mineral acid such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, or an organic acid such as for example ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methane sulfonic acid, and the like.
The compounds of the invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purpose of the invention.
The present invention further provides pharmaceutical compositions comprising a hexafluoroisopropanol derivative having the general Formula I, or a pharmaceutically acceptable salt thereof, in admixture with one or more pharmaceutically acceptable auxiliaries, and optionally other therapeutic agents. The term “acceptable” means being compatible with the other ingredients of the composition and not deleterious to the recipients thereof. Compositions include e.g. those suitable for oral, sublingual, subcutaneous, intravenous, epidural, intrathecal, intramuscular, transdermal, pulmonary, local, or rectal administration, and the like, all in unit dosage forms for administration. For oral administration, the active ingredient may be presented as discrete units, such as tablets, capsules, powders, granulates, solutions, suspensions, and the like. For parenteral administration, the pharmaceutical composition of the invention may be presented in unit-dose or multi-dose containers, e.g. injection liquids in predetermined amounts, for example in sealed vials and ampoules, and may also be stored in a freeze dried (lyophilized) condition requiring only the addition of sterile liquid carrier, e.g. water, prior to use.
Mixed with one or more pharmaceutically acceptable auxiliaries, e.g. as described in the standard reference, Gennaro, A. R. et al., Remington: The Science and Practice of Pharmacy (20th Edition., Lippincott Williams & Wilkins, 2000, see especially Part 5: Pharmaceutical Manufacturing), the active agent may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules, suppositories or patches. By means of pharmaceutically acceptable liquids the active agent can be applied as a fluid composition, e.g. as an injection preparation, in the form of a solution, suspension, emulsion, or as a spray, e.g. a nasal spray.
For making solid dosage units, the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated. In general any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used. Suitable carriers with which the active agent of the invention can be administered as solid compositions include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts. For parenteral administration, aqueous suspensions, isotonic saline solutions and sterile injectable solutions may be used, containing pharmaceutically acceptable dispersing agents and/or wetting agents, such as propylene glycol or butylene glycol.
The invention further includes a pharmaceutical composition, as hereinbefore described, in combination with packaging material suitable for said composition, said packaging material including instructions for the use of the composition for the use as hereinbefore described.
The hexafluoroisopropanol derivatives of the present invention were found to be modulators of LXRα and/or LXRβ, especially having agonistic activity thereon, and are as such useful in preventing and reducing the risk of atherosclerosis and related disorders associated with cholesterol and bile acids transport and metabolism, such as hypercholesterolemia (e.g. coronary heart disease), cholesterol gallstones, lipid storage diseases, diabetes and obesity.
The compounds of the invention are potentially also useful in further indications such as:
Inflammatory Disease:
Ligand activation of LXR has been shown to inhibit a number of inflammatory pathways e.g. Interleukin1-β, Interleukin-6, cyclooxygenase-2 and most recently shown to directly inhibit C-reactive protein expression. See Blaschke et al., Circ. Res. 99: 88-99. (2006). Compounds of the invention may have therapeutic utility in suppression of inflammation in inflammatory diseases such as contact dermatitis (see Fowler et al., J. Invest. Dermatol. 120:246-55. (2003); neuroinflammatory diseases such as multiple sclerosis (Zhang-Gandhi and Drew. J. Neuroimmunol. 183:50-59. (2007)) and autoimmune encephalomyelitis. See Hindinger et al., J. Neurosci. Res. 84:1225-1234 (2006).
Proliferative Vascular Disease:
The LXR ligand T0901317 has been shown to inhibit vascular smooth muscle cell proliferation and neointima formation following balloon injury in vitro and in vivo. Compounds of the invention may therefore have therapeutic utility in proliferative vascular diseases. See Blaschke et al., Circ. Res. 95:110-123 (2004).
Diabetes/Metabolic Syndrome:
Recent literature has demonstrated efficacy of LXR agonists in animal models of insulin resistance and diabetes and thus compounds of the invention may have potential therapeutic utility in the treatment of diabetes and metabolic syndrome (see Liu et al., Endocrinology. 147:5061-5068 (2006); Fernandez-Veledo et al., Diabetologia. 49:3038-3048 (2006)).
Cancer:
The LXR agonist T0901317 delayed progression of tumours in an animal model of prostate cancer. Compounds of the invention may be potentially useful for treatment of prostate cancer. See Chuu et al., Cancer. Res. 66:6482-6486 (2006).
Neurodegenerative Disease:
Via modulation of cellular cholesterol levels, LXR agonists can reduce the deposition of β-amyloid in the brain. In addition T0901317 has been shown to lower deposition of β-amyloid but also improve memory. See Riddell et al., Mol. Cell. Neurosci. 34: 621-628 (2007). The agonist derivatives of the present invention may therefore have therapeutic utility in neurodegenerative diseases such as Alzheimers disease.
Combination Therapies:
The compounds of the invention may be combined with another therapeutic agent that is useful in the treatment of other metabolic disorders such as; hypertension, hyperlipidaemias, dyslipidaemias, diabetes, chronic inflammatory disorders, obesity and in any condition where enhancement of reverse cholesterol transport and/or improvement of LDL:HDL ratios would be of potential clinical benefit. Examples of such therapies are: inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG CoA reductase) (e.g. atorvastatin, pravastatin, simvastatin, lovastatin, rosuvastatin and others), cholesterol absorption inhibitors (e.g. ezetimibe), bile sequestrants (e.g. cholestyramine), microsomal triglyceride transfer protein (MTP) inhibitors, peroxisome proliferator-activated receptor modulators (e.g. muraglitazar, rosiglitazone, fibrates and others), cholesterol ester transfer protein inhibitors, nicotinic acid derivatives (e.g. Niaspan® etc), Acyl coenzyme A: cholesterol acyl transferase (ACAT) inhibitors (e.g. eflucimibe), farnesoid X receptor modulators, therapies used for the treatment of metabollic syndrome or type 2 diabetes e.g. mefformin. Compounds of the invention may be combined with anti-inflammatory therapies (e.g. aspirin) and with treatments for neurodegenerative diseases (e.g Aricept®, Exelon®, Reminyl® and Ebixa®).
The compounds of the invention may be administered for humans in a sufficient amount and for a sufficient amount of time to alleviate the symptoms. Illustratively, daily dosage levels for humans can be in the range of 0.001-50 mg per kg body weight, preferably in a daily dosage of 0.01-20 mg per kg body weight.
The invention is illustrated by the following Examples.